A virus-induced conformational switch of STAT1-STAT2 dimers boosts antiviral defenses

Cell Res. 2021 Feb;31(2):206-218. doi: 10.1038/s41422-020-0386-6. Epub 2020 Aug 5.

Abstract

Type I interferons (IFN-I) protect us from viral infections. Signal transducer and activator of transcription 2 (STAT2) is a key component of interferon-stimulated gene factor 3 (ISGF3), which drives gene expression in response to IFN-I. Using electron microscopy, we found that, in naive cells, U-STAT2, lacking the activating tyrosine phosphorylation, forms a heterodimer with U-STAT1 in an inactive, anti-parallel conformation. A novel phosphorylation of STAT2 on T404 promotes IFN-I signaling by disrupting the U-STAT1-U-STAT2 dimer, facilitating the tyrosine phosphorylation of STATs 1 and 2 and enhancing the DNA-binding ability of ISGF3. IKK-ε, activated by virus infection, phosphorylates T404 directly. Mice with a T-A mutation at the corresponding residue (T403) are highly susceptible to virus infections. We conclude that T404 phosphorylation drives a critical conformational switch that, by boosting the response to IFN-I in infected cells, enables a swift and efficient antiviral defense.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Chlorocebus aethiops
  • Fibroblasts / metabolism
  • Fibroblasts / virology
  • HEK293 Cells
  • HeLa Cells
  • Herpes Simplex / metabolism*
  • Herpes Simplex / virology
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Phosphorylation / genetics
  • Protein Conformation
  • Protein Multimerization / genetics*
  • RNA Interference
  • Rhabdoviridae Infections / metabolism*
  • Rhabdoviridae Infections / virology
  • STAT1 Transcription Factor / chemistry*
  • STAT1 Transcription Factor / metabolism
  • STAT2 Transcription Factor / chemistry*
  • STAT2 Transcription Factor / genetics
  • STAT2 Transcription Factor / metabolism
  • Signal Transduction / genetics*
  • Simplexvirus / metabolism*
  • Vero Cells
  • Vesicular stomatitis Indiana virus / metabolism*

Substances

  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT2 Transcription Factor
  • STAT2 protein, human
  • Stat1 protein, mouse
  • Stat2 protein, mouse